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EP0037781B1 - Phenyl alcoxy propanol amines, their preparation and their use as medicines - Google Patents

Phenyl alcoxy propanol amines, their preparation and their use as medicines Download PDF

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Publication number
EP0037781B1
EP0037781B1 EP81400533A EP81400533A EP0037781B1 EP 0037781 B1 EP0037781 B1 EP 0037781B1 EP 81400533 A EP81400533 A EP 81400533A EP 81400533 A EP81400533 A EP 81400533A EP 0037781 B1 EP0037781 B1 EP 0037781B1
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Prior art keywords
formula
radical
process according
prepared
propanol
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EP81400533A
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German (de)
French (fr)
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EP0037781A1 (en
Inventor
Gilbert Dr. Chim. Mouzin
Henri Dr. Chim. Cousse
Pol Vilain
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Pierre Fabre SA
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Pierre Fabre SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
    • C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
    • C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds

Definitions

  • the present invention carried out at the Pierre FABRE Research Center, relates to new derivatives of phenyl alkoxy propanolamines, their manufacturing process and their therapeutic application, in particular in the treatment of hypertension and angina pectoris.
  • the invention also relates to pharmaceutical compositions containing these derivatives used as active ingredients.
  • the active ingredients currently marketed, having a beta-blocking activity have the general structure:
  • the mineral or organic acids capable of giving therapeutically acceptable salts with the compounds of general formula 1 are, for example hydrochloric acid, sulfuric acid, phosphoric acid, succinic acid, oxalic acid, tartaric acid, maleic acid or fumaric acid.
  • lower alkyl means an alkyl radical containing from 1 to 8 and preferably from 1 to 4 carbon atoms.
  • beta-blocking, anti-arrhythmic, anti-calcium activities which are useful in the treatment of various diseases of cardiac origin.
  • the invention also relates to a process for preparing the compounds of general formula I by reaction of a glycidyl ether of formula II on a primary amine of formula III in a solvent, in particular an alcohol such as methanol.
  • the glycidyl ether of formula II can be prepared by epichlorohydrin on an alcohol of formula IV in the presence of a base, such as sodium hydroxide, and a catalyst of the quaternary ammonium type, such as a compound of formula in which R o is a lower alkyl radical and X ° the anion of an acid, for example HSO 3 ⁇ or Hal ⁇ , such as in particular tetrabutylammonium hydrogen sulfate.
  • a base such as sodium hydroxide
  • a catalyst of the quaternary ammonium type such as a compound of formula in which R o is a lower alkyl radical and X ° the anion of an acid, for example HSO 3 ⁇ or Hal ⁇ , such as in particular tetrabutylammonium hydrogen sulfate.
  • the residual oil is taken up in ether, washed with bicarbonate water and then with water saturated with sodium chloride.
  • Solubilities Soluble in water at 10% and 15% in dimethyl sulfoxide.
  • the previously described chemical compounds have been subjected to toxicity controls.
  • the toxicity study was carried out in conventional mice weighing 20 to 22 grams. The substances were administered intravenously and orally.
  • the LD 50 are calculated according to the method of K ⁇ RBER G. - Arch. Exptl. Pathol. Pharmacol., 1931, 162, 480.
  • the LD 50 is between 25 and 100 mg / kg. By oral route, the LD 50 is between 600 and 1200 mg / kg.
  • the most interesting products significantly reduce isoprenal tachycardia from the dose of 1 mg / kg intravenously.
  • these compounds Given their beta-blocking property and their low toxicity, these compounds can be used in therapeutics and more particularly in the treatment of hypertension.
  • compositions in which the active principle is mixed with non-toxic diluents or vehicles pharmaceutically acceptable.
  • compositions can be administered orally, parenterally, intravenously, or rectally.
  • compositions may for example be in the form of tablets, capsules, suppositories, aqueous or oily solutions, aqueous or oily suspensions, emulsions, dispersible powders or injectable aqueous or oily solutions or suspensions.
  • compositions according to the invention may contain, in addition to the compounds of general formula I, other active ingredients which complement or reinforce their therapeutic actions.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

1. Claims for the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE Novel derivatives of phenyl alcoxy propanol amines having the general formula I : see diagramm : EP0037781,P13,F1 in which : X represents a hydrogen atom, a lower alkyl radical and more particularly the methyl radical, a lower alcoxy radical and more particularly the methoxy radical, n represents the values 1 - 3, and R represents an isopropyl or terbutyl radical, such that their salts with mineral or organic acids are therapeutically acceptable. 1. Claims for the Contracting State : AT Process for preparing compounds of the general formula I : see diagramm : EP0037781,P14,F1 in which : X represents a hydrogen atom, a lower alkyl radical and more particularly the methyl radical, a lower alcoxy radical and more particularly the methoxy radical, n represents the values 1 - 3, and R represents an isopropyl or terbutyl radical, such that their salts with mineral or organic acids are therapeutically acceptable, characterised in that a glycidyl ether of the formula II : see diagramm : EP0037781,P14,F2 in which X and n have the significations given above, is reacted in a solvent medium, in particular an alcohol such as methanol, on a primary amine of the formula III : R-NH2 in which R has the signification given previously.

Description

La présente invention, réalisée au Centre de Recherches Pierre FABRE, a pour objet de nouveaux dérivés de phényl alcoxy propanolamines, leur procédé de fabrication et leur application en thérapeutique, notamment dans le traitement de l'hypertension et de l'angor.The present invention, carried out at the Pierre FABRE Research Center, relates to new derivatives of phenyl alkoxy propanolamines, their manufacturing process and their therapeutic application, in particular in the treatment of hypertension and angina pectoris.

L'invention vise également les compostitions pharmaceutiques contenant ces dérivés utilisés comme principes actifs.The invention also relates to pharmaceutical compositions containing these derivatives used as active ingredients.

Les principes actifs actuellement commercialisés, possédant une activité béta-bloquante, présentent la structure générale:

Figure imgb0001
The active ingredients currently marketed, having a beta-blocking activity, have the general structure:
Figure imgb0001

Ce sont des éthers de phénols, il était donc imprévisible que les dérivés éthers d'alcools présentent le même type d'activité béta-bloquante.These are phenol ethers, so it was unpredictable that the alcohol ethers would exhibit the same type of beta-blocking activity.

Pour illustrer l'arrière plan technologique de l'objet de la présente invention, on mentionnera par exemple les documents de technique antérieure suivants: Die Pharmazie, vol. 26, n° 8, août 1971, H. Schulz et al.: Darstellung von herz- und kreislaufwirksamen Verbindungen, page 477 -481, page 477 et tables 4-5; DD-A-56 533 (Schulz, Jassmann et Forster); BE-A-699 789 (VEB Fahlberg-List Magdeburg, chemische und pharmazeutische Fabriken); Chemicals Asstracts, vol. 83, n° 7, 18 août 1975, page 464, abrégé 58414t t Colombus Ohio US et JP-A-7 512 039 (Tanable Seiyaku Co LTD) 07-02-1975, abrégé.To illustrate the technological background of the object of the present invention, mention will be made, for example, of the following prior art documents: Die Pharmazie, vol. 26, No. 8, August 1971 H. Schulz et al .: Darstellung von Herz- und Verbindungen kreislaufwirksamen page 477 -481, page 477 and Table 4-5; DD-A-56,533 (Schulz, Jassmann and Forster); BE-A-699 789 (VEB Fahlberg-List Magdeburg, chemische und pharmazeutische Fabriken); Chemicals Abstracts, vol. 83, No. 7, August 18, 1975, page 464, abstract 58414t t Colombus Ohio US and JP-A-7 512 039 (Tanable Seiyaku Co LTD) 07-02-1975, abstract.

La présente invention a pour objet de nouveaux dérivés de phényl alcoxy propanolamines de formule générale 1:

Figure imgb0002
dans laquelle:

  • X représente un hydrogène, un radical alcoyle inférieur et plus particulièrement le radical méthyle, un radical alcoxy inférieur et plus particulièrement le radical méthoxy,
  • n représente les valeurs 1 à 3, et
  • R représente un radical isopropyle ou terbutyle,

ainsi que leurs sels avec les acides minéraux ou organiques thérapeutiquement acceptables.The subject of the present invention is new derivatives of phenyl alkoxy propanolamines of general formula 1:
Figure imgb0002
 in which:
  • X represents a hydrogen, a lower alkyl radical and more particularly the methyl radical, a lower alkoxy radical and more particularly the methoxy radical,
  • n represents the values 1 to 3, and
  • R represents an isopropyl or terbutyl radical,

as well as their salts with therapeutically acceptable mineral or organic acids.

Les acides minéraux ou organiques susceptibles de donner des sels thérapeutiquement acceptables avec les composés de formule générale 1, sont par exemple l'acide chlorhydrique, l'acide sulfurique, l'acide phosphorique, l'acide succinique, l'acide oxalique, l'acide tartrique, l'acide maléique ou l'acide fumarique.The mineral or organic acids capable of giving therapeutically acceptable salts with the compounds of general formula 1 are, for example hydrochloric acid, sulfuric acid, phosphoric acid, succinic acid, oxalic acid, tartaric acid, maleic acid or fumaric acid.

Dans le cadre de la présente invention on entendra par alcoyle inférieur un radical alcoyle contenant de 1 à 8 et de préférence de 1 à 4 atomes de carbone.In the context of the present invention, the term lower alkyl means an alkyl radical containing from 1 to 8 and preferably from 1 to 4 carbon atoms.

Ces dérivés sont doués d'activités béta-bloquantes, anti-arythmique, anti-calcium qui sont utiles dans le traitement de diverses maladies d'origine cardiaque.These derivatives are endowed with beta-blocking, anti-arrhythmic, anti-calcium activities which are useful in the treatment of various diseases of cardiac origin.

L'invention concerne également un procédé de préparation des composés de formule générale I par réaction d'un glycidyl éther de formule Il

Figure imgb0003
sur une amine primaire de formule III
Figure imgb0004
dans un solvant, en particulier un alcool tel que le méthanol.The invention also relates to a process for preparing the compounds of general formula I by reaction of a glycidyl ether of formula II
Figure imgb0003
 on a primary amine of formula III
Figure imgb0004
 in a solvent, in particular an alcohol such as methanol.

Conformément à la présente invention, le glycidyl éther de formule Il peut être préparé par de l'épichlorhydrine sur un alcool de formule IV

Figure imgb0005
en présence d'une base, telle que la soude, et d'un catalyseur du type ammonium quaternaire, tel qu'un composé de formule
Figure imgb0006
dans laquelle Ro est un radical alcoyle inférieur et X° l'anion d'un acide, par exemple HSO3⊖ ou Hal⊖, tel qu'en particulier l'hydrogénosulfate de tétrabutylammonium.In accordance with the present invention, the glycidyl ether of formula II can be prepared by epichlorohydrin on an alcohol of formula IV
Figure imgb0005
 in the presence of a base, such as sodium hydroxide, and a catalyst of the quaternary ammonium type, such as a compound of formula
Figure imgb0006
 in which R o is a lower alkyl radical and X ° the anion of an acid, for example HSO 3 ⊖ or Hal⊖, such as in particular tetrabutylammonium hydrogen sulfate.

Dans les formules II, III et IV les différents radicaux ont la même signification que les radicaux correspondants de la formule générale 1.In formulas II, III and IV the different radicals have the same meaning as the corresponding radicals of general formula 1.

On notera que les différents composés de formules III et IV sont connus dans la technique antérieure et/ou peuvent être facilement obtenus par des procédés en soi connus.It will be noted that the various compounds of formulas III and IV are known in the prior art and / or can be easily obtained by methods known per se.

Les composés chimiques suivants et leur mode de préparation sont cités à titre d'exemples non limitatifs.The following chemical compounds and their method of preparation are cited by way of nonlimiting examples.

Exemple 1Example 1 Préparation de l'isopropylamino-3, m-tolyl méthoxy-1 propanol-2 fumaratePreparation of isopropylamino-3, m-tolyl methoxy-1 propanol-2 fumarate a) Préparation du méta méthyl benzyloxy-1, époxy-2-3 propanea) Preparation of meta methyl benzyloxy-1, epoxy-2-3 propane

A un milieu hétérogène de 50 ml d'épichlorhydrine, 50 ml de soude à 50% et 1,36 g d'hydrogénosulfate de tétrabutylammonium, on introduit en 20 minutes 12,2 g (0,1 mole) de métaméthylbenzylalcool, en refroidissant sur bain de glace.To a heterogeneous medium of 50 ml of epichlorohydrin, 50 ml of 50% sodium hydroxide and 1.36 g of tetrabutylammonium hydrogen sulphate, 12.2 g (0.1 mole) of metamethylbenzyl alcohol are introduced in 20 minutes, while cooling ice bath.

Après deux heures sous forte agitation, on ajoute 100 ml d'eau et on extrait deux fois à l'éther. La phase organique est lavée avec une solution bicarbonatée, puis à l'eau et on sèche sur sulfate de sodium.After two hours with vigorous stirring, 100 ml of water are added and the mixture is extracted twice with ether. The organic phase is washed with a bicarbonate solution, then with water and dried over sodium sulfate.

Après filtration et évaporation du solvant, on obtient avec un rendement quantitatif l'époxyde intermédiaire.After filtration and evaporation of the solvent, the intermediate epoxide is obtained with a quantitative yield.

b) préparation de l'isopropyl-3 métatolylméthoxy-1 propanol-2 fumarateb) preparation of 3-isopropyl-1-metatolylmethoxy-2-propanol fumarate

A une solution de 10 g de métaméthylbenzyloxy-1 époxy-2-3 propane (0,0056 mole) dans 100 ml de méthanol absolu, refroidie par un bain de glace, on ajoute sous agitation 17 ml (11,82 g ou 0,2 mole) d'isopropylamine. On laisse une nuit à température ambiante sous forte agitation, et on évapore jusqu'à siccité.To a solution of 10 g of metamethylbenzyloxy-1 epoxy-2-3 propane (0.0056 mole) in 100 ml of absolute methanol, cooled by an ice bath, 17 ml (11.82 g or 0, 2 moles) of isopropylamine. It is left overnight at room temperature with vigorous stirring, and evaporated to dryness.

L'huile résiduelle est reprise par l'éther, on lave à l'eau bicarbonatée puis à l'eau saturée de chlorure de sodium.The residual oil is taken up in ether, washed with bicarbonate water and then with water saturated with sodium chloride.

La solution éthérée est séchée sur sulfate de sodium, après filtration on traite par 3,65 g (0,03 mole) d'acide fumarique, on récupère après filtration et séchage 83% de produit de formule:

Figure imgb0007

  • Formule brute: C18H27N O6
  • Masse moléculaire: 353,4
  • Cristaux: blancs
  • Point de fusion:104°C
  • Spectre de RMN (DMSO-d6) δ ppm: 1,25 (d, 6H); 2,3 (s, 3H); 2,7 à 3,7 (m, 5H); 4 (m, 1 H); 4,45 (s, 2H);
  • 6,55 (s, 2H); 7,1 (s, 4H); 9,2 (s, 2H) échangeables.
The ethereal solution is dried over sodium sulphate, after filtration, treatment is carried out with 3.65 g (0.03 mol) of fumaric acid, 83% of product of formula:
Figure imgb0007
  • Gross formula: C 18 H 27 NO 6
  • Molecular mass: 353.4
  • Crystals: white
  • Melting point: 104 ° C
  • NMR spectrum (DMSO-d 6 ) δ ppm: 1.25 (d, 6H); 2.3 (s, 3H); 2.7-3.7 (m, 5H); 4 (m, 1H); 4.45 (s, 2H);
  • 6.55 (s, 2H); 7.1 (s, 4H); 9.2 (s, 2H) exchangeable.

Chromatographie sur plaque:

  • - support: gel de silice 60 F 254 Merck
  • - solvant: chloroforme - méthanol - ammoniaque 80/18/2
  • - révélation: 0,5
  • - Rf: 0,5
Plate chromatography:
  • - support: silica gel 60 F 254 Merck
  • - solvent: chloroform - methanol - ammonia 80/18/2
  • - revelation: 0.5
  • - Rf: 0.5

Solubilités: Soluble dans l'eau à 10% et à 15% dans le diméthylsulfoxyde.Solubilities: Soluble in water at 10% and 15% in dimethyl sulfoxide.

Exemple 2Example 2 Préparation du tertiobutylamino-3 métatolylméthoxy-1 propanol-2 maléatePreparation of tertiobutylamino-3 metatolylmethoxy-1 propanol-2 maleate

D'une façon similaire à celle décrite dans l'exemple 1, mais en utilisant la tertiobutylamine et l'acide maléique comme agent salifiant, on obtient le produit de formule:

Figure imgb0008

  • Formule brute: C19H29N O6
  • Masse moléculaire: 367,4
  • Cristaux: blancs
  • Point de fusion: 108° C
  • Spectre RMN (DMSO-d6): δ ppm: 1,3 (s, 9H); 2,3 (s, 3H); 2,4 à 3,3 (m, 2H); 3,5 (d, 2H); 4 (m, 1 H); 4,5
  • (s, 2H); 6,15 (s, 2H); 7,15 (s, 4H).
  • Chromatographie sur plaque:
    • - support: gel de silice 60 F 254 Merck
    • - solvant: chloroforme - méthanol - ammoniaque 80/18/2
    • - révélation: UV et iode
    • - Rf: 0,5
  • Solubilités: Soluble dans l'eau à 2,5% et à 10% dans le diméthylsulfoxyde.
In a similar manner to that described in Example 1, but using tert-butylamine and maleic acid as salifying agent, the product of formula is obtained:
Figure imgb0008
  • Gross formula: C 19 H 29 NO 6
  • Molecular mass: 367.4
  • Crystals: white
  • Melting point: 108 ° C
  • NMR spectrum (DMSO-d 6 ): δ ppm: 1.3 (s, 9H); 2.3 (s, 3H); 2.4 to 3.3 (m, 2H); 3.5 (d, 2H); 4 (m, 1H); 4.5
  • (s, 2H); 6.15 (s, 2H); 7.15 (s, 4H).
  • Plate chromatography:
    • - support: silica gel 60 F 254 Merck
    • - solvent: chloroform - methanol - ammonia 80/18/2
    • - revelation: UV and iodine
    • - Rf: 0.5
  • Solubilities: Soluble in water at 2.5% and 10% in dimethyl sulfoxide.

Exemple 3Example 3 Préparation de l'isopropylamino-3 (orthométhoxy benzyloxy)-1 propanol-2 fumaratePreparation of isopropylamino-3 (orthomethoxy benzyloxy) -1 propanol-2 fumarate

D'une manière similaire à celle décrite dans l'exemple 1, mais en utilisant l'orthométhoxy benzylalcool, on obtient le produit de formule:

Figure imgb0009

  • Formule brute: C18H27N 07
  • Masse moléculaire: 369,4
  • Cristaux: blancs
  • Point de fusion: 110° C
  • Chromatographie sur plaque:
    • - support: gel de silice 60 F 254 Merck
    • - solvant: chloroforme - méthanol - ammoniaque 80/18/2
    • - révélation: UV et iode
    • - Rf: 0,50
  • Solubilités: Soluble dans l'eau à 10% et dans le diméthylsulfoxyde à 15%.
In a similar manner to that described in Example 1, but using orthomethoxy benzyl alcohol, the product of formula is obtained:
Figure imgb0009
  • Gross formula: C 18 H 27 N 0 7
  • Molecular mass: 369.4
  • Crystals: white
  • Melting point: 110 ° C
  • Plate chromatography:
    • - support: silica gel 60 F 254 Merck
    • - solvent: chloroform - methanol - ammonia 80/18/2
    • - revelation: UV and iodine
    • - Rf: 0.50
  • Solubilities: Soluble in water at 10% and in dimethyl sulfoxide at 15%.

Exemple 4Example 4 Préparation du tertiobutylamino-3 (orthométhoxy benzyloxy)-1 propanol-2 maléatePreparation of tertiobutylamino-3 (orthomethoxy benzyloxy) -1 propanol-2 maleate

D'une façon similaire à celle décrite dans l'exemple 3, mais en utilisant la tertiobutylamine et l'acide maléique comme agent salifiant, on obtient le produit de formule:

Figure imgb0010

  • Formule brute: C19H29N O7
  • Masse moléculaire: 383,4
  • Cristaux: blancs
  • Point de fusion: 104°C
  • Chromatographie sur plaque:
    • - support: gel de silice 60 F 254 Merck
    • - solvant: méthanol - chloroforme - ammoniaque 80/18/2
    • - révélation: UV et iode
    • - Rf: 0,54
  • Solubilités: Soluble dans l'eau à 10%, soluble dans le diméthylsulfoxyde à 15%.
In a similar manner to that described in Example 3, but using tert-butylamine and maleic acid as salifying agent, the product of formula is obtained:
Figure imgb0010
  • Gross formula: C 19 H 29 NO 7
  • Molecular mass: 383.4
  • Crystals: white
  • Melting point: 104 ° C
  • Plate chromatography:
    • - support: silica gel 60 F 254 Merck
    • - solvent: methanol - chloroform - ammonia 80/18/2
    • - revelation: UV and iodine
    • - Rf: 0.54
  • Solubilities: Soluble in water at 10%, soluble in dimethyl sulfoxide at 15%.

Exemple 5Example 5 Préparation du tertiobutylamino-3 (métaméthoxybenzyloxy)-1 propanol-2 maléatePreparation of tertiobutylamino-3 (metamethoxybenzyloxy) -1 propanol-2 maleate

D'une façon similaire à celle décrite dans l'exemple 1, mais en utilisant le métaméthoxy benzyl alcool, la tertiobutylamine et l'acide maléique comme agent salifiant, on obtient le produit de formule:

Figure imgb0011

  • Formule brute: C19H29N 07
  • Masse moléculaire: 383,4
  • Cristaux: blancs
  • Point de fusion: 89° C
  • Chromatographie sur plaque:
    • - support: gel de silice 60 F 254 Merck
    • - solvant: chloroforme - méthanol - ammoniaque 80/18/2
    • - révélation: UV et iode
    • - Rf: 0,65
  • Solubilités: Soluble dans l'eau à 10%, soluble dans le diméthylsulfoxyde à 12%.
In a similar manner to that described in Example 1, but using metamethoxy benzyl alcohol, tert-butylamine and maleic acid as salifying agent, the product of formula is obtained:
Figure imgb0011
  • Gross formula: C19H29N 0 7
  • Molecular mass: 383.4
  • Crystals: white
  • Melting point: 89 ° C
  • Plate chromatography:
    • - support: silica gel 60 F 254 Merck
    • - solvent: chloroform - methanol - ammonia 80/18/2
    • - revelation: UV and iodine
    • - Rf: 0.65
  • Solubilities: Soluble in water at 10%, soluble in dimethyl sulfoxide at 12%.

Exemple 6Example 6 Préparation du tertiobutylamino-3 (paraméthoxy benzyloxy)-1 propanol-2 maléatePreparation of tertiobutylamino-3 (paramethoxy benzyloxy) -1 propanol-2 maleate

D'une façon similaire à celle décrite dans l'exemple 1, mais en utilisant le paraméthoxy benzylalcool, la tertiobutylamine et l'acide maléique comme agent salifiant, on obtient le produit de formule:

Figure imgb0012

  • Formule brute: C19H29N O7
  • Masse moléculaire: 383,4
  • Cristaux: blancs
  • Point de fusion: 102°C
  • Chromatographie sur plaque:
    • - support: gel de silice 60 F 254 Merck
    • - solvant: chloroforme - méthanol ― ammoniaque 80/18/2
    • - révélation: UV et iode
    • - Rf: 0,63
  • Solubilités: Soluble dans l'eau à 10%, soluble dans le diméthylsulfoxyde à 20%.
In a similar manner to that described in Example 1, but using paramethoxy benzylalcohol, tertiobutylamine and maleic acid as salifying agent, the product of formula is obtained:
Figure imgb0012
  • Gross formula: C 19 H 29 NO 7
  • Molecular mass: 383.4
  • Crystals: white
  • Melting point: 102 ° C
  • Plate chromatography:
    • - support: silica gel 60 F 254 Merck
    • - solvent: chloroform - methanol - ammonia 80/18/2
    • - revelation: UV and iodine
    • - Rf: 0.63
  • Solubilities: Soluble in water at 10%, soluble in dimethyl sulfoxide at 20%.

Exemple 7Example 7 Préparation de l'isopropylamino-3 (phényl-3 propoxy)-1 propanol-2 fumaratePreparation of 3-isopropylamino (3-phenyl propoxy) -1 2-propanol fumarate

D'une façon similaire à celle décrite dans l'exemple 1, mais en utilisant le phényl-3 propanol-1, on obtient le produit de formule:

Figure imgb0013

  • Formule brute: C19H29N O6
  • Masse moléculaire: 367,4
  • Cristaux: blancs
  • Point de fusion : 86,5° C
  • Chromatographie sur plaque:
    • - support: gel de silice 60 F 254 Merck
    • - solvant: chloroforme - méthanol - ammoniaque 80/18/2
    • - révélation: UV et iode
    • - Rf: 0,50
  • Solubilités: Soluble dans l'eau à 10%, et dans le diméthylsulfoxyde à 12%.
In a similar manner to that described in Example 1, but using 3-phenyl-propanol-1, the product of formula is obtained:
Figure imgb0013
  • Gross formula: C 19 H 29 NO 6
  • Molecular mass: 367.4
  • Crystals: white
  • Melting point: 86.5 ° C
  • Plate chromatography:
    • - support: silica gel 60 F 254 Merck
    • - solvent: chloroform - methanol - ammonia 80/18/2
    • - revelation: UV and iodine
    • - Rf: 0.50
  • Solubilities: Soluble in water at 10%, and in dimethyl sulfoxide at 12%.

Exemple 8Example 8 Préparation du tertiobutylamino-3 (phényl-3 propoxy)-1 propanol-2 fumaratePreparation of tert-butylamino-3 (3-phenyl propoxy) -1 propanol-2 fumarate

D'une façon similaire à celle décrite dans l'exemple 1, mais en utilisant le phényl-3 propanol-1 et la tertiobutylamine, on obtient le produit de formule:

Figure imgb0014

  • Formule brute: C20H31N O6
  • Masse moléculaire: 381,4
  • Cristaux: blancs
  • Point de fusion: 90° C
  • Chromatcgraphie sur plaque:
    • - support: gel de silice 60 F 254 Merck
    • - solvant: chloroforme - méthanol - ammoniaque 80/18/2
    • - révélation: UV et iode
    • - Rf: 0,50
  • Solubilités: Soluble à 10% dans l'eau, à 15% dans le diméthylsulfoxyde.
In a similar manner to that described in Example 1, but using 3-phenyl-propanol-1 and tert-butylamine, the product of formula is obtained:
Figure imgb0014
  • Gross formula: C 20 H 31 NO 6
  • Molecular mass: 381.4
  • Crystals: white
  • Melting point: 90 ° C
  • Chromatography on plate:
    • - support: silica gel 60 F 254 Merck
    • - solvent: chloroform - methanol - ammonia 80/18/2
    • - revelation: UV and iodine
    • - Rf: 0.50
  • Solubilities: 10% soluble in water, 15% in dimethylsulfoxide.

Les propriétés béta-bloquantes des composés de formule générale 1 ont pu être mises en évidence à l'aide de l'expérimentation suivante.The beta-blocking properties of the compounds of general formula 1 could be demonstrated using the following experiment.

ExperimentationExperimentation A) ToxicologieA) Toxicology

Les composés chimiques précédemment décrits ont été soumis à des contrôles de toxicité. L'étude de la toxicité a été effectuée chez la souris conventionnelle pesant de 20 à 22 grammes. Les substances ont été administrées par voie intraveineuse et orale.The previously described chemical compounds have been subjected to toxicity controls. The toxicity study was carried out in conventional mice weighing 20 to 22 grams. The substances were administered intravenously and orally.

Les DL50 sont calculées selon la méthode de KÂRBER G. - Arch. Exptl. Pathol. Pharmacol., 1931,162, 480.The LD 50 are calculated according to the method of KÂRBER G. - Arch. Exptl. Pathol. Pharmacol., 1931, 162, 480.

Par voie intraveineuse les DL50 sont comprises entre 25 et 100 mg/kg. Par voie orale les DL50 sont comprises entre 600 et 1200 mg/kg.Intravenously the LD 50 is between 25 and 100 mg / kg. By oral route, the LD 50 is between 600 and 1200 mg / kg.

B) Etude pharmacologiqueB) Pharmacological study

Les expérimentations pharmacologiques auxquelles ont été soumis les composés chimiques objet de l'invention ont permis de mettre en évidence d'intéressantes propriétés béta-bloquantes.The pharmacological experiments to which the chemical compounds which are the subject of the invention have been subjected have made it possible to highlight interesting beta-blocking properties.

MéthodeMethod

Tachycardie isoprénalique chez le chien (DUNLOP O. et SHANK P. - Brit. J. Pharmacol., 1968, 32, 201 à 218).Isoprenal tachycardia in dogs (DUNLOP O. and SHANK P. - Brit. J. Pharmacol., 1968, 32, 201 to 218).

Les produits les plus intéressants réduisent significativement la tachycardie isoprénalique à partir de la dose de 1 mg/kg par voie intraveineuse.The most interesting products significantly reduce isoprenal tachycardia from the dose of 1 mg / kg intravenously.

C) Applications thérapeutiquesC) Therapeutic applications

Compte tenu de leur propriété béta-bloquante et de leur faible toxicité, ces composés peuvent être utilisés en thérapeutiques et plus particulièrement dans le traitement de l'hypertension.Given their beta-blocking property and their low toxicity, these compounds can be used in therapeutics and more particularly in the treatment of hypertension.

Ces composés peuvent être utilisés sous la forme de compositions pharmaceutiques dans lesquelles on mélange le principe actif avec des diluants ou véhicules non toxiques pharmaceutiquement acceptables. Ces compositions peuvent être administrées par voie orale, parentérale, intraveineuse, ou rectale.These compounds can be used in the form of pharmaceutical compositions in which the active principle is mixed with non-toxic diluents or vehicles pharmaceutically acceptable. These compositions can be administered orally, parenterally, intravenously, or rectally.

Les compositions peuvent être par exemple sous la forme de comprimés, de capsules, de suppositoires, de solutions aqueuses ou huileuses, de suspensions aqueuses ou huileuses, d'émulsions, de poudres dispersables ou de solutions ou suspensions aqueuses ou huileuses injectabies.The compositions may for example be in the form of tablets, capsules, suppositories, aqueous or oily solutions, aqueous or oily suspensions, emulsions, dispersible powders or injectable aqueous or oily solutions or suspensions.

Les compositions pharmaceutiques selon l'invention peuvent contenir, outre les composés de formule générale I, d'autres principes actifs venant compléter ou renforcer leurs aktions thérapeutiques.The pharmaceutical compositions according to the invention may contain, in addition to the compounds of general formula I, other active ingredients which complement or reinforce their therapeutic actions.

Claims (16)

1. Process for preparing compounds of the general formula I:
Figure imgb0040
in which:
X represents a hydrogen atom, a lower alkyl radical and more particularly the methyl radical, a lower alcoxy radical and more particularly the methoxy radical,
n represents the values 1-3, and
R represents an isopropyl or terbutyl radical,
such that their salts with mineral or organic acids are therapeutically acceptable,

characterised in that a glycidyl ether of the formula II:
Figure imgb0041
in which X and n have the significations given above, is reacted in a solvent medium, in particular an alcohol such as methanol, on a primary amine of the formula III:
Figure imgb0042
in which R has the signification given previously.
2. Process according to claim 1, characterised in that the glycidyl ether of the formula II is prepared by reaction, in the presence of a base and of a catalyst, of epichlorhydrin on an alcohol of the formula IV:
Figure imgb0043
in which X and n have the significations given in claim 1.
3. Process according to claim 2, characterised in that the catalyst is a quaternary ammonium compound of the general formula:
Figure imgb0044
in which:
Ro represents an alkyl, and
X represents HSO3- or Hal-.
4. Process according to claim 3, characterised in that the quaternary ammonium compound is the hydrogen sulphate of tetrabutylammonium.
5. Process according to claim 2, characterised in that the base used is a mineral base and more particularly soda.
6. Process according to any one of claims 1 to 5, characterised in that the 3-isopropylamino meta-tolyl 1-methoxy 2-propanol fumarate of the formula I is prepared.
7. Process according to any one of claims 1 to 5, characterised in that the 3-tertiobutylamino meta-tolyl 1-methoxy 2-propanol maleate of the formula I is prepared.
8. Process according to any one of claims 1 to 5, characterised in that the 3-isopropylamino 1-(ortho-methoxy benzyloxy) 2-propanol fumarate of the formula I is prepared.
9. Process according to any of claims 1 to 5, characterised in that the 3-tertiobutylamino 1 -(ortho-methoxy benzyloxy) 2-propanol maleate of the formula I is prepared.
10. Process according to any one of claims 1 to 5, characterised in that the 3-tertiobutylamino 1-(meta-methoxy benzyloxy) 2-propanol maleate of the formula I is prepared.
11. Process according to any one of claims 1 to 5, characterised in that the 3-tertiobutylamino 1-(para-methoxy benzyloxy) 2-propanol maleate of the formula I is prepared.
12. Process according to any one of claims 1 to 5, characterised in that the 3-isopropylamino 1-(3-phenyl propoxy) 2-propanol fumarate of the formula I is prepared.
13. Process according to any one of claims 1 to 5, characterised in that the 3-tertiobutylamino 1-(3-phenyl propoxy) 2-propanol fumarate of the formula I is prepared.
EP81400533A 1980-04-04 1981-04-02 Phenyl alcoxy propanol amines, their preparation and their use as medicines Expired EP0037781B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT81400533T ATE5813T1 (en) 1980-04-04 1981-04-02 PHENYL-ALCOXY-PROPANOLAMINE, THEIR PRODUCTION AND USE AS A MEDICINAL PRODUCT.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR8007717 1980-04-04
FR8007717A FR2479814A1 (en) 1980-04-04 1980-04-04 PHENYL ALCOXY PROPANOLAMINES, THEIR PREPARATION AND THEIR APPLICATION AS MEDICAMENTS

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EP0037781A1 EP0037781A1 (en) 1981-10-14
EP0037781B1 true EP0037781B1 (en) 1984-01-11

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FR2575158B1 (en) * 1984-12-20 1987-10-02 Pf Medicament ARYLALCOYLOXYMETHYL-2 MORPHOLINS, THEIR PREPARATION AND THEIR APPLICATION AS MEDICAMENTS USEFUL IN THE TREATMENT OF CENTRAL NERVOUS SYSTEM DISORDERS
US4959390A (en) * 1988-12-15 1990-09-25 E. I. Du Pont De Nemours And Company Polyhydroxybenzyloxypropanolamines

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ATE5813T1 (en) 1984-01-15
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ES500821A0 (en) 1982-01-01
DE3161866D1 (en) 1984-02-16
ES8201532A1 (en) 1982-01-01

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